Susceptibility to many diseases, suspected to be of autoimmune origin, is linked to genes of the immunoglobulin supergene family. These genes include the class II genes of the major histocompatibility complex, the immunoglobulin genes, and the genes encoding the antigen-specific receptor on T lymphocytes. We will study three diseases, including myasthenia gravis and pemphigus vulgaris, that are clear examples of autoimmune conditions mediated by antibody, and multiple sclerosis, a putative autoimmune neurologic disease. We will study associations between MHC class II genes, immunoglobulin genes, and TcR genes and these diseases using RFLP analysis and genomic sequencing, utilizing the polymerase chain reaction technology. We have seen that associations between class II HLA genes, immunoglobulin heavy chain allotype and T cell receptor genotype and susceptibility to disease, are often maintained in individuals with these diseases of different ethnic backgrounds. These data provide strong support for a direct participation for these genes in autoimmune disease, since it is unlikely that an allele linked to susceptibility would have remained in linkage with the same alleles across ethnic boundaries. We will study patients with MS, MG and PV in North America, Japan, Australia, France, Austria, and Israel (Arab and Jew). These associations between immunoglobulin supergenes and disease have been exploited in order to design new therapeutic approaches from human autoimmune disease that have shown results in treating autoimmune conditions in laboratory animals including rhesus monkeys.